Abstract | BACKGROUND: The highly selective α2 -adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti-inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre-clinical newborn neuroprotection studies is unknown. METHODS: Following cerebral hypoxia-ischaemia, dexmedetomidine was administered to nine newborn piglets in a de-escalation dose study in combination with hypothermia (whole body cooling to 33.5°C). Dexmedetomidine was administered with a loading dose of 1 μg/kg and maintenance infusion at doses from 10 to 0.6 μg/kg/h. One additional piglet was not subjected to hypoxia-ischaemia. Blood for pharmacokinetic analysis was sampled pre-insult and frequently post-insult. A one-compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non-linear mixed effects modelling. RESULTS: All dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4-0.8 μg/l). Seven out of the nine piglets with hypoxia-ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1 μg/l. Dexmedetomidine clearance was 0.126 l/kg/h [coefficient of variation (CV) 46.6.%] and volume of distribution was 3.37 l/kg (CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5°C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia-ischaemia. CONCLUSIONS:
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Authors | M Ezzati, K Broad, G Kawano, S Faulkner, J Hassell, B Fleiss, P Gressens, I Fierens, J Rostami, M Maze, J W Sleigh, B Anderson, R D Sanders, N J Robertson |
Journal | Acta anaesthesiologica Scandinavica
(Acta Anaesthesiol Scand)
Vol. 58
Issue 6
Pg. 733-42
(Jul 2014)
ISSN: 1399-6576 [Electronic] England |
PMID | 24724965
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2014 The Authors. The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd. |
Chemical References |
- Adrenergic alpha-2 Receptor Agonists
- Neuroprotective Agents
- Dexmedetomidine
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Topics |
- Adrenergic alpha-2 Receptor Agonists
(blood, pharmacokinetics, therapeutic use)
- Animals
- Asphyxia Neonatorum
(complications)
- Dexmedetomidine
(blood, pharmacokinetics, therapeutic use)
- Disease Models, Animal
- Hypothermia, Induced
- Hypoxia-Ischemia, Brain
(drug therapy, etiology)
- Male
- Metabolic Clearance Rate
- Neuroprotective Agents
(blood, pharmacokinetics, therapeutic use)
- Nonlinear Dynamics
- Sus scrofa
- Swine
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